DE19915576A1 - New equilenine derivatives, useful as antioxidative estrogenic hormonal steroids for e.g. prophylactic geriatrics in women and men - Google Patents

Abstract

Equilenine derivatives (I) are new. Equilenine derivatives of formula (I) are new. R1 = H, 1-5C alkyl, 1-5C acyl or benzoyl; R2 = H and R2' = H, F, OH or 1-5C acyloxy; or R2 +R2' = oxo; R3 = H or Me; R4 = H and R4' = OH or 1-11C acyloxy; or R4+R4' = oxo, methylene, halomethylene or a dihalomethylene; R5 = H or Me. An Independent claim is also included for the preparation of (I).

Description

The present invention relates to new Equileninderiva te, process for their preparation and these connections drugs containing genes.

Equilenin itself is an estrogenic steroid, which is made up of the urine of pregnant mares can be obtained.

The new equilenin derivatives according to the invention have a Oxygen function at C atom 11 and an α-permanent methy lenbrücke between the C atoms 14 and 15. Equilenin are derivatives with an oxygen function on the C atom 11 known. So racemic 11-oxo-equilenin methyl ether obtained by total synthesis (Tetrahedron Lett. 2763 (1967); Aust. J. Chem. 23, 547 (1970); J. Org. Chem. 39, 2193 (1974)). Racemi was also totally synthetic 11-Oxo-3-methoxy-estra-1,3,5 (10), 6,8,14-hexaen-17β- yl-carboxylic acid available (Tetrahedron Lett. 479 (1968)). 14α, 17α-bridged equiline derivatives with an 11- Oxygen functions were partially synthesized. The Introduction of the 11-oxygen function into the molecule followed with cerium IV ammonium nitrate (Tetrahedron Lett. 35, 8599 (1994)). Equilenin derivatives with an α- or β- permanent methylene bridge between the C atoms 14 and 15 were also produced partially synthetically, whereby the B-ring with dichlorodicyano-benzoquinone (DDQ) dehy was third (Tetrahedron Lett. 35, 2329 (1994)).

The object of the present invention is to create new ones Equiline derivatives and a process for their preparation to make available.  

According to the invention, this object is achieved in that equilenin derivatives of the general formula I

be created,
in the
R _{1 represents} a hydrogen atom, a C ₁ to C ₅ alkyl or a C ₁ to C ₅ acyl group or a benzoyl group,
R _{2 represents} a hydrogen atom and R ₂ 'represents a hydrogen atom, a fluorine atom, a hydroxy group or a C ₁ to C ₅ acyloxy group
or R ₂ and R ₂ 'together represent an oxo group,
R _{3 represents} a hydrogen atom or a methyl group,
R _{4 represents} a hydrogen atom and R ₄ 'represents a hydroxy group or a C ₁ to C ₁₁ acyloxy group or R ₄ and R ₄ ' together represent an oxo group, a methylene group, a halogen methylene group or a dihalomethylene group and
R _{5 is} a hydrogen atom or a methyl group.

It is preferred according to the invention if R _{5 is} a hydrogen atom.

Equiline derivatives which are particularly preferred according to the invention are, for example:
14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3,11β, 17β-triol,
11β, 17β-dihydroxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3-yl-benzoate,
11β, 17β-dihydroxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3-yl-propionate,
3,11β-dihydroxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-17β-yl decanoate,
3,11β-dihydroxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-17-one,
3-methoxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-11α, 17β-diyl-diacetate,
15β-methyl-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3,11β, 17β-triol,
3,17β-dihydroxy-11β-fluoro-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen,
3,17β-dihydroxy-14α, 15α-methylene-1,3,5 (10), 6,8-pentaen-11-one,
3-methoxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-11α, 17α-diyl-diacetate,
3-methoxy-14α, 15α-methylene-11-oxo-estra-1,3,5 (10), 6,8-pentaen-17α-yl acetate,
11β-hydroxy-17,17-difluoromethylene-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3-yl-3-benzoate and
14α, 15α, 17,17-bis-methylene-estra-1,3,5 (10), 6,8-pentaen-3,11α-diol.

The equiline derivatives according to the invention are new. she have so far neither been produced nor become their own described.

The equiline derivatives according to the invention have antioxidants active activity with low systemic hormonal activity kung on. The antioxidant effect was among others by inhibiting the iron-II-catalyzed lipid peroxidati on in synaptosomal membrane fractions of the rat, inhibition copper-II-sulfate-induced LDL cholesterol Oxidation and inhibition of xanthine oxidase and various that of other monooxygenases. Systemic Estrogenic effects were shown in the Allen-Doisy test at the council checked. The measured spectrum of effects of the inventions Equilenin derivatives according to the invention offers possibilities for a therapeutic application in all those cases in which cause oxygen radicals related to Diseases of organs or tissues are available. A before The main field of application is geroprophylaxis Women and - due to the low feminizing Effect of the connections - also in men.

The compounds according to the invention can both administered orally and parenterally. At the ora len application are prodrugs in the form of carboxylic acid esters are particularly beneficial as they are long lasting enable constant active ingredient levels.

The present invention also relates to a process for the preparation of the equilenin derivatives of the general formula I according to the invention:

wherein R ₁ , R ₂ , R ₂ ', R ₃ , R ₄ , R ₄ ' and R _{5 have} the meaning given above,
by using a compound of general formula II

wherein R ₁ , R ₂ , R ₂ ', R ₃ , R ₄ , R ₄ ' and R _{5 have} the meaning given above,
with diphosphorus tetraiodide in the presence of pyridine to react and react the compounds thus obtained to the compounds of general formula I in a manner known per se.

It is known that diphosphorus tetraiodide reacts with epoxides and alcohols. For example, epoxides can be reduced to olefins with diphosphorus tetraiodide (Synthesis 905 (1978); Nouv. J. Chem. 3, 745 (1979)). Alcohols react with diphosphorus tetraiodide to form iodides (Tetrahedron Letters 1801 (1979); JCS Chem. Commun. 229 (1983)) or with elimination to form olefins (Helv. Chim. Acta 11,106 (1928)) or to cumulenes (Ber. 71, 1899 (1938); ibid. 85, 386 (1952); ibid. 87, 598 (1954); JCS Chem. Commun. 885 (1975)). The process according to the invention is characterized in that the action of diphosphate tetraiodide on compounds of the general formula II leads to the elimination of the 8,9-oxido group and at the same time to the introduction of an additional double bond between the C atoms 6 and 7. This enables the production of the equilenin derivatives of the general formula I according to the invention from compounds of the general formula II in one step and avoids an additional reaction step for introducing the 6,7-double bond (Tetrahedron Letters 35, 2329 (1994)). The process according to the invention is further characterized in that - provided compounds of the general formula II, in which R ₂ is hydrogen and R ₂ 'is a hydroxyl group, are used - neither an elimination of the unprotected hydroxyl group to the olefin in question nor a substitution the hydroxyl group is made by iodine. The course and the high selectivity of the process according to the invention are surprising and were not predictable by the person skilled in the art.

Compounds of the general formula II are accessible from compounds of the general formula III in which R ₁ and R ₃ to R _{5 have} the meanings given under compound II, by treating them with excess peroxycarboxylic acid.

The equiline derivatives obtained according to the invention can optionally be further structurally modified by methods known per se. For example, it is possible to subject compounds of the general formula I in which R ₂ 'denotes an α-hydroxy group and R _{2 denotes} a β-hydrogen to oxidation with activated dimethyl sulfoxide in a manner known per se, the corresponding 11-oxo compounds arise, the reduction with a complex metal hydride gives the corresponding 11β-hydroxy derivatives. Alternatively, the reaction of compounds of the general formula I in which R ₂ 'denotes an α-hydroxy group and R ₂ denotes a β-hydrogen with diethylamino-sulfur trifluoride (DAST) leads to compounds with an 11β-fluorine group. Compounds of the general formula I, in which R _{1 represents} a C ₁ - to C ₅ -alkyl radical, can be converted into the free phenols in a manner known per se using boron tribromide or diisobutylaluminum hydride. Compounds of the general formula I, in which R ₄ 'is an α-hydroxy group and R _{4 is} a β-hydrogen, can be oxidized in a manner known per se with activated dimethyl sulfoxide, giving the corresponding 17-oxosteroids, the reduction of which with borane or oxazaborolidines gives the corresponding 17β-hydroxy compounds.

The cyclopropano steroids of the general formula II

in the
R _{1 represents} a hydrogen atom, a C ₁ to C ₅ alkyl or a C ₁ to C ₅ acyl group or a benzoyl group,
R _{2 represents} a hydrogen atom and R ₂ 'represents a hydrogen atom, a fluorine atom, a hydroxyl group or a C ₁ to C ₅ acyloxy group or R ₂ and R ₂ ' together represent an oxo group,
R _{3 represents} a hydrogen atom or a methyl group,
R _{4 represents} a hydrogen atom and R ₄ 'represents a hydroxy group or a C ₁ to C ₁₁ acyloxy group or R ₄ and R ₄ ' together represent an oxo group, a methylene group, a halogen methylene group or a dihalomethylene group and
R _{5 is} a hydrogen atom or a methyl group, are new and have not been described so far.

The following cyclopropano steroids mentioned by way of example are particularly preferred.
3-methoxy-14α, 15α-methylene-8α, 9α-oxido-estra-1,3,5 (10) - trien-17α-ol,
3-methoxy-14α, 15α-methylene-8α, 9α-oxido-estra-1,3,5 (10) - trien-17α-yl acetate,
3-methoxy-14α, 15α-methylene-8α, 9α-oxido-18a-homo-estra-1,3,5 (10) -triene-17α-yl-propionate,
14α, 15α-methylene-8α, 9α-oxido-estra-1,3,5 (10) -triene-3,17α-diyl-diacetate,
3-methoxy-15β-methyl-14α, 15α-methylene-8α, 9α-oxido-estra-1,3,5 (10) -trien-17β-ol,
11α-hydroxy-3-methoxy-14α, 15α-methylene-8α, 9α-oxido-estra-1,3,5 (10) -trien-17α-yl acetate,
3-methoxy-14α, 15α-methylene-8α, 9α-oxido-oxido-estra-1,3,5 (10) - triene-11α, 17α-diyl-diacetate and
3-methoxy-11α-hydroxy-8α, 9α-oxido-14α, 15α-methylene-estra-1,3,5 (10) -trien-17β-yl acetate.

These compounds represent new intermediates Equiline derivatives according to the invention and are thus another object of the present invention.

The present invention also relates to medicines agent for oral, transdermal, rectal, subcutaneous, intravenous or intramuscular application, besides usual carriers and diluents a compound of the general formula I as an active ingredient.

The pharmaceuticals of the invention are made with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical technical auxiliaries according to the desired Ap type of application with a suitable dosage in known  Manufactured way. The preferred preparations are in a dosage form that ge for oral application is suitable. Such dosage forms are, for example Tablets, film-coated tablets, coated tablets, capsules, pills, pul ver, solutions or suspensions or depot forms.

Of course, parenteral preparations also come like injection solutions. Furthermore, be as Preparations also called suppositories, for example.

Appropriate tablets can for example by Mi rule the active ingredient with known excipients for example inert diluents such as dextrose, sugar, Sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or Talk and / or means to achieve a deposit effect such as carboxyl polymethylene, carboxylmethyl cellulose, Cellu Loose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers hen.

Correspondingly, coated tablets can be coated by analog the cores usually produced in tablets in Dragee covers used means, for example Po lyvinylpyrrolidone or shellac, gum arabic, talc, Titanium dioxide or sugar. It can the coated tablet also consists of several layers, where in the excipients mentioned above for the tablets can be applied.

Solutions or suspensions with the invention Active ingredient can additionally taste enhancing agents such as saccharin, cyclamate or sugar and z. B. aroma contain substances such as vanillin or orange extract. she can also suspending aids such as sodium carboxy  methyl cellulose or preservatives such as p-hydroxy benzoates included. Capsules containing active ingredients can for example, be made by the effect substance with an inert carrier such as milk sugar or sor bit mixes and encapsulates in gelatin capsules.

Suitable suppositories can be found, for example Mix with the appropriate carriers such as New tralfetten or polyethylene glycol or their derivatives produce.

Transdermal forms of application can, for example, consist of plasters containing active ingredient. Such systems are known.

The following examples illustrate the invention.

example 1 11α-hydroxy-3-methoxy-14α, 15α-methylene-8α, 9α-oxido- estra-1,3,5 (10) -triene-17α-yl acetate from 3-methoxy-14α, 15α-methylene-estra-1,3,5 (10), 8- tetraen-17α-yl acetate.

A solution of the steroid tetraene (3.5 g) in dichloromethane (120 ml) is mixed with peroxyacetic acid (32%, 5.5 ml) at room temperature. The reaction mixture is left to stand at room temperature overnight. Thereafter, the solution is treated successively with aqueous sodium thiosulfate solution (20%), saturated aqueous sodium hydrogen carbonate solution and with water. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is subjected to flash chromatography on silica gel (eluent: cyclohexane: ethyl acetate 3: 2 v / v). Recrystallization from acetone / n-hexane gives the title compound.
Mp 159-162.5 ° C
¹ H-NMR (CDCl ₃ / TMS): 7.80 (d, J = 8.8 Hz, H-1), 6.79 (dd, J = 8.8, 2.8 Hz, H-2) , 6.65 (d, J = 2.8 Hz, H-4), 4.93 (q, J = 7.9 Hz, H-11), 4.78 (d, J = 5.9 Hz, H-17), 3.80 (s, -OCH ₃ ), 2.03 (s, -OOC-CH ₃ ), 1.11 (dd, J = 5.4, 3.2 Hz, 14.15- CH ₂ -), 0.88 (s, H-18), 0.69 (ddd, J = 6.6, 5.4, 1, Hz, 14.15-CH ₂ -).
MS (m / z): 354 (M ⁺ ), 336, 294, 277, 261.

Example 2 3-methoxy-14α, 15α-methylene-8α, 9α-oxido-estra-1,3,5 (10) - triene-11α, 17α-diyl diacetate from 11α-hydroxy-3-methoxy-14α, 15α-methylene-8α, 9α-oxido- estra-1,3,5 (10) -triene-17α-yl acetate

Acetanydride (4 ml) and dimethylaminopyridine (0.04 g) are added to a solution of the 11α-hydroxysteroids (0.4 g) in pyridine (4 ml) at room temperature. The mixture is stirred for 3 hours at room temperature and then poured into ice water. The resulting precipitate is filtered off, washed neutral with water and air-dried. The title compound is obtained by flash chromatography on silica gel (eluent: cyclohexane: ethyl acetate 7: 3 v / v).
Mp 151-154 ° C
¹ H-NMR (CDCl ₃ / TMS): 7.80 (d, J = 8.8 Hz, H-1), 6.79 (dd, J = 8.8, 2.8 Hz, H-2) , 6.65 (d, J = 2.8 Hz, H-4), 9.93 (q, J = 7.9 Hz, H-11), 4.78 (d, J = 5.9 Hz, H-17), 3.80 (s, -OCH ₃ ), 2.03 (s, -OOC-CH ₃ ), 1.11 (dd, J = 5.4, 3.2 Hz, 14.15- CH ₂ -), 0.88 (s, H-18), 0.69 (ddd, J = 6.6, 5.4, 1.7 Hz, 14.15-CH ₂ -).
MS (m / z): 354 (MR ⁺ ), 336, 294, 277, 261.

Example 3

3-methoxy-14α, 15α-methylethylene-estra-10,6,8-pentaen 11α, 17α-diyl diacetate from 3-methoxy-14α, 15α-methylene-8α, 9α-oxido-estra- 1,3,5 (10) -triene-11α, 17α-diyl-diacetate

A solution consisting of the steroid diacetate (0.1 g), chloroform (2.4 ml) and pyridine (0) is added to a stirred suspension of diphosphorus tetraiodide (0.14 g) in chloroform (2.4 ml) under argon protection and at room temperature , 24 ml) was added dropwise. The mixture is then heated to boiling under reflux for 13 hours. Water is added, the organic phase is separated off and the aqueous phase is exhaustively extracted with chloroform. The combined organic phases are washed successively with hydrochloric acid (1 N), water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is subjected to flash chromatography, the title compound being obtained as a foam.
¹ H NMR (CDCl ₃ / TMS): 7.66 (d, J = 8.8 Hz, H-6.7), 7.58 (d, J = 9.5 Hz, H-1), 7 , 17 (dd, J = 9.5, 2.8 Hz, H-2), 7.13 (d, J = 2.8 Hz, H-4), 6.85 (d, J = 8.8 Hz, H-6.7), 6.78 (q, J = 8.1 Hz, H-11), 4.98 (d, J = 6.1 Hz, H-17), 3.92 (s , -OCH ₃ ), 2.11 (s, -OOC-CH ₃ ), 2.09 (s, -OOC-CH ₃ ), 1.46 (dd, J = 4.9, 3.2 Hz, 14 , 15-CH ₂ -), 0.97 (s, H-18) 0.57 (ddd, J = 8.2, 4.9, 1.7 Hz, 14.15-CH ₂ -).
MS (m / z): 394 (M ⁺ ), 334, 274, 259.

Example 4 11α-hydroxy-3-methoxy-14α, 15α-methylene-estra- 1,3,5 (10), 6,8-pentaen-17α-yl acetate from 11α-hydroxy-3-methoxy-14α, 15α-methylene-8α, 9α-oxido- estra-1,3,5 (10) -triene-17α-yl acetate

Analogously to Example 3, the 11-hydroxy compound is treated with diphosphorus tetraiodide, the amorphous titanium compound being obtained.
¹ H NMR (CDCl ₃ / TMS): 8.26 (d, J = 9.4 Hz, H-1), 7.62 (d, J = 8.3 Hz, H-6, 7), 7 , 22 (dd, J = 9.4, 2.7 Hz, H-2), 7.12 (d, J = 2.7 Hz, H-4), 6.83 (d, J = 8.3 Hz, H-6, 7), 5.68 (q, J = 7.7 Hz, H-11), 4.99 (d, J = 6.3 Hz, H-17), 3.92 (s , -OCH ₃ ), 2.10 (s, -OOC-CH ₃ ), 0.93 (s, H-18), 0.57 (ddd, J = 7.6, 9.8, 1.6 Hz , 14,15-CH ₂ -).
MS (m / z): 370 (M ⁺ ), 353, 310, 292, 277, 267.

Claims (5)

1. Equilenin derivatives of the general formula I:
in the
R _{1 represents} a hydrogen atom, a C ₁ to C ₅ alkyl or a C ₁ to C ₅ acyl group or a benzoyl group,
R _{2 represents} a hydrogen atom and R ₂ 'represents a hydrogen atom, a fluorine atom, a hydroxyl group or a C ₁ - to C ₅ -acyloxy group or R ₂ and R ₂ ' together represent an oxo group,
R _{3 represents} a hydrogen atom or a methyl group,
R _{4 represents} a hydrogen atom and R ₄ 'represents a hydroxyl group or a C ₁ to C ₁₁ acyloxy group or R ₄ and R ₄ ' together represent an oxo group, a methylene group, a halomethylene group or a dihalogenomethylene group and
R _{5 is} a hydrogen atom or a methyl group. 2. Equilenin derivatives according to claim 1, characterized in that R _{5 is} a hydrogen atom. 3. Equilenin derivatives according to claim 1, namely
14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3,11β, 17β-triol,
11β, 17β-dihydroxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3-yl-benzoate,
11β, 17β-dihydroxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3-yl-propionate,
3,11β-dihydroxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-17β-yl decanoate,
3,11β-dihydroxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-17-one,
3-methoxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-11α, 17β-diyl-diacetate,
15β-methyl-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3,11β, 17β-triol,
3,17β-dihydroxy-11β-fluoro-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen,
3,17β-dihydroxy-14α, 15α-methylene-1,3,5 (10), 6,8-pentaen-11-one,
3-methoxy-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-11α, 17α-diyl-diacetate,
3-methoxy-14α, 15α-methylene-11-oxo-estra-1,3,5 (10), 6,8-pentaen-17α-yl acetate,
11β-hydroxy-17,17-difluoromethylene-14α, 15α-methylene-estra-1,3,5 (10), 6,8-pentaen-3-yl-3-benzoate and
14α, 15α, 17,17-bis-methylene-estra-1,3,5 (10), 6,8-pentaen-3,11α-diol. 4. Process for the preparation of equiline derivatives of the general formula I:
wherein R ₁ , R ₂ , R ₂ ', R ₃ , R ₄ , R ₄ ' and R _{5 have} the meaning given in claim 1 by using a compound of the general formula II:
wherein R ₁ , R ₂ , R ₂ ', R ₃ , R ₄ , R ₄ ' and R _{5 have} the meaning given in claim 1, with diphosphorus tetraiodide in the presence of pyridine and the compounds thus obtained in a manner known per se to the compounds of the general formula I according to claim 1. 5. Medicinal products characterized by a content of at least one compound according to claim 1.